### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM



### Date :

Subje ct:

From:

Through:

T o : 23-April-20 1 4



### Flutriafol : H uman-Health Risk Assessment for Tolerances for Residue s in/on F i e ld Com, Popcorn, Peanut, Wheat, Strawberries, C ucu rbit Vegetables, F rui t ing Vegetables, and T r ee Nuts.

PC C ode: 1 28940 DP Barcodes: D 411 360, 412161 Decision Nos.: 475694, 478287 Registration N os

. : 67760-75 and 67760- 12 0 Peti t ion Nos.: 3F8156 and 3F8174 Regulatory Act ion: Sectio n 3 Registrat i ons Risk Assessment Type: single chemical C a se No. : 7060
TXR No.: not applicable CAS N o.: 76674-21-0 MRID No : not applicable 40 CFR: 180 .62 9



### Tom Bloem,

# Chemis**~ ~**  / Kelly M. Lo we, Environmental Scientist 

# /1/J'JBt/ 

# ;t

.. /

.

_# r//L_/ / "' Anwar Y. 

### Dunbar, Ph

. D., Pharmacologist**~/ ,.**  

### ·
. Risk Assess men t Branch 1 ( RAB 1 ) Health E ffects Division (HE D ; 7509P)

Char l es W. Smith III

, Branc h

# hi**ef ~~**  George F. Kramer

, Ph.D.

, Senior

# Ch**iiliSt ~-:**  RABl/HED (7509P)

Hope Johnson/T a m ue Gibson, RM 21 Registration Division (RD; 7505P)

HED of the O ffic e of Pesticide Programs (OPP) is c harged with es timating the risk t o human heal th from exposure to p estici des. RD o f OPP has reques t ed t ha t HED eva l uate hazard and

exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk t o human health that will result f r om all r egis t e r e d and proposed us es of flutr ia fol ( ( ± 

### )

- a -(2- fluoroph eny l)-a-( 4- fluorophenyl) -1 H-1

, 2

, 4

- triazo l e -1-

e thanol). A su mm a ry of the fi ndin gs and an assessment of human r isk resulting from the

r eg i s tered and proposed uses for flutriafol are provided in th i s doc u men t. The risk assessment, dietary ri s k assessment, and residue chemistry review were pro vide d by Tom Bloem (RABl)

, the ha zar d characterization was provided by A nwar Dunbar (RAB 1 ), the occupational/residential

ex po s ure (ORE) and ri s k assessment were provided by Kelly Lowe, and the drinki ng water

assessment was provid ed by James K. Wo l f of the Environmental Fate a nd E ffec t s Di visio n (EFED).

Page I of38F l utr i afo l H u m an-Hea l t h Risk Assessment D 4 11 360



### T able of C ontent s

1.0 Executive Summary

.......................................... .. .. .. .. .. .. .. . .. .. .. .......... . ... .. .. .. . .. .. .... . .. . ... .. . .. .. ... . ...... . ..................... 3

2.0 Recommendations

...................................................................................................................... . .... . ... . ............. 6

2.1 Data Deficie n cies/Data Needs

........ . ........... . ...................................................... .. .. .. ...................... . ................. 6 2.2 T olerance Conside r ations

............................................................................................................. . .................. 7 2.2.1 Enforcement Analytica l Method

........................ . ............................................................. .. ................. 7 2.2.2 Recomme n ded Tole r ances

........................................................................................... . .. ... ................. 

### 8
2.2.3 Revisions to Petitione d- Fo r Tolerances

................................................................... . .. .. .. .. ....... .. ......... 9 2.2.4 I nternational H armonization

...... . ....................... . ... . ... . ...................... . ...................... . ...... ... .. . ... .. ... .. ... . 9 2.3 Label Recommendations

................ . ....... . .......... . . .......... . ....... . ............................ . .. . ......................................... 9

3.0 I ngred i ent Pr ofile

............... . ...... . . .. .. .. .. .. .. ..... .. .. .. .. ...... . ............................... . ................................... .. ........... .. .. I 0

3. 1 C h e m ica l Identity

.. . ... .. .. .. .... .. .. ... .. .... ... .. .. .............................................................. .. .. .... .... ... .. ............ . ...... .... 10 3.2 P h ysical/C h emica l Pr o p ert ies

.. . . . . . . . ..... . ... . .. . .. . ........ . ... .......................................... . . ... . ... . ... . .. .. .. . .... . ... .. ... .. .. ... I 0 3.3 P roposed Use P attern

. .. .. ............. . .. . ... .. ..... . .. ..... . ... . .............................................. . ... . .. .. .. .. .. .......... .. ....... .. ..... I I 3.4 Ant i c i pa t ed Ex p osure P a t hways

.. .. ...... .. .. ....... . .............. . ........................................... . ..... .. .. .. .. .. .. ... .. ... .. .. ... l3 3.5 Cons i de r ation of Env ir onmen t a l J us t ice

............................................................................... . .... .. .. .. ............. 13

4.0 Hazard Characte r izatio n and Do s e- Response Assessme n t

..................................................... .. ....... .. .. .. ......... 1 4

4.1 Absorption, Distribut i on, Metabolism, & Elimination (ADME)

.................................................................. 1 4 4.2 Toxicological Effects

............................................................................................................ . ....................... 14 4.3 Safety Factor for Infants and Ch il dren (FQ P A SF)

....................................................................................... 16 4.3.1 Completeness of the T oxicology Database

....................................................................................... 16 4.3.2 Evidence of Neurotoxicity

...................................... . ......................................................................... 16 4.3.3 Evidence of Sens i tivity / Susce p t i bi l ity in the Deve l op i ng or Young Anima l

.................................... 16 4.3.4 Residua l Uncertainty in the Ex p osure Database

............................................................................... 17 4.4 Toxicity Endpoint and POD Selections

........................................................................................................ 17 4.5 Recommendation for Combining Routes of Exposure for Risk Assessment..

.............................................. 18

5.0 Dietary Exposure and R i sk Assessment.

......................................................................................................... 20

5. 1 Metabo li te / Degradate Res i d u e Profile

......................................................................................... .. . .. ........... . 20 5.2 Food Residue Profile

... .. . . ... .. .......... . . . ...................................................................................... .. ...... .... . ... .. .. .. 2 1 5.3 Dr i nking Wa t e r R esi d ue Pro fi l e

.. . ... . .. .. .. .................................................................................. . .. .. .. . .... .. .. .. ... 22 5.4 Di eta r y (Food + Dr inki n g Wat e r) R isk A ssess m en t

............................................................................ . .... .. .. 23

6.0 R es i dential (Non-Occupa t i o n a l) Exp o s ure / R isk C h a r acterization

................. . ... . .. . .... ............. .. .. . ........ .. .. ....... 24

6. 1 Spray D r ift

........................ ... . ...... . .. .. ... . .. .. . .. .. .. .. .. .. .... . ... . .................. . ... . ... . ... . ... . ..... .. .. .. ... . .. .. .. ... .. .. ................ 24 6.2 Resident i a l Bys t ander Pos t -A p pli c a t i o n I n h a l ation Ex p osu r e

..................................... .. .. . .. . ............ . ............. 24

7.0 Aggregate Exposure/ R isk Character i zation

............................................................................. .. ... .. ... . ... . ........ 25

8.0 Cumulative Exposure/Risk Characterization

................................................................. . .. . ............................. 25

9.0 Occupational Exposure / Risk Characterization

................................. . ...................................... . ...................... 26

9.1 Handler R isk Assessment..

.... . .............................................................................................................. . ........ 26 9.2 Post-Application Risk Assessment

....... . ... . .. . ........................... . ...................................... . .............................. 29
9.2.1 Inhalat i on P ost-App l ication Risk Assessment..

................................................................................. 29 9.2 .2 Restricted E n try I nterval

...... . ............................................................................................................ 30

Appendix A. Toxico l ogy Profile and Exe c utive Summaries

...................................................................................... 3l

Appendix B. Chemical Names and Structures

........................................................................................................... 37

Page 2 of38

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 3 of 38 

### 1.0 Executive Summary

Flutriafol ((±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol) is a contact and systemic Group 3 triazole fungicide which acts primarily as an inhibitor of ergosterol biosynthesis, thereby interfering with synthesis of fungal cell membranes. T olerances for residues of flutriafol are establi shed in/on the following commodities at 0.01

- 2.4 ppm : banana (import), coffee (import), field

corn, popcorn, sweet corn (rotational crop tolerance), cotton (rotational crop tolerance), grape, peanut, pome fruit (group 11

- 09) , stone fruit (group 12

- 10) , su gar beet

, and soybean

. As a result of secondary residue s, ruminant (cattle, goat, horse, and sheep) and hog meat byproduct to lerances are also established for residues of flutriafol at 0.02

- 0.07 ppm. A Section 18 Emergency Exemption has also be en granted for application of flutriafol to cotton with time

- limited tolerances of 0.35

- 0.50 ppm (expire s on 31

- Dec

- 2014).

Cheminova, Inc. requested Section 3 Registrations and permanent tolerances for residues of fl utriafol in/on strawberries, cucurbit vegetables, fruiting vegetables, tree nuts, wheat, and triticale (see Table 2.2.2.1 for proposed tolerances). In addition, the petitioner is requesting the following amendments to the peanut, field corn, and popcorn registrati ons (see Table 2.2.2.1 for tolerances proposed as a result of these amendments): (1) removal of the peanut hay feeding restriction and (2) reduction in the current 80

- day preharvest interval (PHI) for field corn and popcorn forage, stover, and grain to 0 days for forage and 7 days for stover and grain.

Hazard Assessment: Flutriafol was categorized as having high oral acute toxicity in the mouse (Category II). It has low acute toxicity via the oral, dermal and inhalation routes (Categories III, III,

an d IV, respectively) in rats. It is minimally irritating to the eyes (Category III) and is not a dermal irritant (Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method).

Short

- term, subchronic, and ch ronic flutriafol toxicity studies in rats, mice

, and dogs identified the liver as the target organ. Hepatotoxicity occurred at similar dose levels across several species and durations of exposure. All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Flutriafol is c lassified as “Not likely to be Carcinogenic to Humans” based on the results of the carcinogenicity studies in rats and mice.

The potential impact of in utero and perinatal flutriafol exposure was inves tigated in three developmental toxicity studies (two in rats, one in rabbits) and two multi

- generation reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, a quantitative susceptibility was observed ( delayed ossif ication or non

- ossification of the skeleton in the fetuses) at a lower dose than maternal effects. In the second rat developmental study, a qualitative susceptibility was noted. Although developmental toxicity occurred at the same dose level that elicite d maternal toxicity, the developmental effects (external, visceral, and skeletal malformations; embryo lethality; skeletal variations; a generalized delay in fetal development; and fewer live fetuses) were more severe than the decreased food consumption an d body

- weight gains observed in the dams. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. In the two

- generation reproduction studies, a qualitative susceptibility was also seen. Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the systemic toxicity of the parental animals (decreased body weight and food consumption and liver toxicity). Effects tha t may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 4 of 38 

### subchronic neurotoxicity studies at the highest dose only. These eff ects, however, were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity. This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity in any additional s hort

- term studies in rats, mice, and dogs, or in the long

- term toxicity studies in rats, mice, and dogs. It is also important to note that in the acute neurotoxicity study, for animals that did not die in the study or were sacrificed in extremis, all effects resolved by Day 8.

In the guid eline immunotoxicity study for flutriafol, there was no evidence of i mmunotoxicity up to the highest dose tested.

All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Several triazoles are carcinogenic. Even though structure

- activity

- relationship (SAR) analysis indicates that flutriafol has the potential to produce thyroid and /or liver tumors in rodents, neither the chronic/carcinogenicity study in rats or the carcinogenicity study in mice revealed treatment

- related increases in tumor incidences.

F ood Quality Protection Act (F QPA ) Safety Factor ( SF ) Decision: The flutriafol risk assessment

team concludes that the 10x FQPA SF should be reduced to 1x since the toxicology database is adequate for assessment of the proposed/registered uses, flutriafol is not considered to be neurotoxic, there are clear NOAELs for the observed fe tal/offspring effects

, and the conservative nature o f the dietary exposure analyses are unlikely to underestimate exposure ( tolerance

- level residues and 100% crop treated; no residential uses).

Dose Response Assessment: T ables 4.3.1 and 4.3.2 provide s a summar y of toxicological doses and endpoints used for assessment of dietary and occupational exposure, respectively, to flutriafol. The rabbit developmental study (no

- observed adverse

- effect level (NOAEL) = 7.5 mg/kg/day) was selected for assessment of acute dietary (females 13

- 49 years old) and short

- /intermediate

- term occupational dermal/inhalation exposures. The neurotoxicity screening battery (NOAEL = 250 mg/kg/day) study was selected for assessment of acute dietary (all populations excluding femal es 13

- 49 years old) exposure. The chronic toxicity (dog) study was s e lected for assessment of chronic dietary exposure. For all exposure scenarios, a 100x uncertainty factor (UF) was applied ( 10 x interspecies extrapolation ; 1 0 x for intraspecies variation ; 1x FQPA SF ( when applicable ) ).

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption I ntake Database (DEEM

- FCID, ver. 3.16) which incorporates the food consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA; 2003

- 2008). The acute and ch ronic analyses assumed tolerance

- level residues or tolerance

- level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted which indicate that tolerances for residues in/on apple juice, grape juice, dried prunes, and tomato puree are unnecessary and since tolerances for residues in/on raisin s and tomato paste are established/recommended , the DEEM (ver

. 7.81) default processin g factors for these commodities were reduced to 1. The DEEM (ver. 7.81) default processing factors were retained for the remaining relevant commodities. The resulting acute ( ≤31 % acute population

- adjusted dose ( aPAD ) ; females 13

- 49 years o ccupied the highest % of the aPAD ) and chronic ( ≤51 % cPAD; children (1

- 2 years old) had the highest exposure ) dietary risk estimates are not of concern to HED.

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 5 of 38 

### Residential (Non

- Occupational) Exposure and Risk Assessment: There are no residential uses proposed or c urrently registered for flutriafol. Therefore, residential handler and post

- application exposure/risk were not assessed.

Aggregate

- Risk Estimates: In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major s ources: food, drinking water, and residential exposures. Because there are no uses for flutriafol which result in residential (non

- occupational) exposures, the aggregate assessment need only consider food and drinking water. Since the dietary exposure

a nalysis included both food and drinking water , the discussion and exposure estimates presented in Section 5.4 represent aggregate acute and chronic exposure to flutriafol and those metabolites identified as being toxicologically identical to flutriafol. A ll aggregate flutriafol risk estimates are not of concern to HED.

Application of flutriafol also results in exposure to T (1,2,4

- triazole) and TA (triazolylalanine), TAA (t riazolylacetic acid), and TLA ( triazole lactic acid) . These compounds are consid ered to be toxicologically different from flutriafol. HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than HED’s level of concern (D 414952 , T. Morton

, 24

- Oct

- 201 3 ). The proposed new uses and label amendments do not require a revision to this m ost recent aggregate assessment.

Occupational Exposure and Risk Assessment: A quantitative assessment of occupational exposure has been conducted for all of the proposed uses ; however, it was determined that an exposure assessment was not necessary for the corn amendment since corn is a registered use site and has been assessed previously. The proposed changes do not impact the use pattern or application rate for the register ed use on corn, and, therefore, a revised occupational exposure assessment is not required. The previous corn assessment determined that provided applicators w ore gloves and a 5

- day reentry interval (REI) is established for detasseling corn, the resulting margins of exposure ( MOEs ) were not of concern to HED (these restrictions are on the proposed label).

The occupational hand ler exposure and risk estimates for the remaining crops indicate that the short

and intermediate

- term dermal and inhalation comb ined MOEs are not of concern to HED (i.e., MOE

> 1 00) with the use of chemical

- resistant gloves as directed by the label. At the baseline level of personal protection (i.e., no gloves and no respirator), only one scenario results in a risk estimate below the LOC with a combined (dermal + inhalation) MOE of 8 2 ; this scenario is mixing/loading a liquid formulation for aerial application to high

- acreage crops. With the addition of gloves, the combined dermal + inhalation MOE is 470, which is not of concern. All other scenarios result in risk estimates greater than 220 with baseline attire.

The occupational post

- application dermal exposure and risk estimates are greater than the LOC of 100 on the day of application , ranging from 230 to 4,600 depending on crop and activity. Since the post

- application assessment is not a concern on Day 0 (12 hours following application), the REI is based on the acute toxicity of flutriafol technical material. Flutriafol has low acute toxicity via the oral, dermal and inhal ation routes (Toxicity Categories III and IV)

, is minimally irritating to the eyes (Toxicity Category III)

, and is not a dermal irritant (Toxicity Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). Therefore, the acute toxicity categories for this chemical require a 12

- hour REI under 40 CFR 156.208 (c)(2)(iii). The 12

- hour
REI for activities other than detasseling corn , which currently appears on the label s, is adequate for the proposed uses

.

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 6 of 38 

### Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for flutriafol at this time. If new policies or procedures are put into place, the Agency may revisit the nee d for a quantitative occupational post

application inhalation exposure assessment for flutriafol

.
Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations.”

Review of Human Research : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the fol lowing Agency website s: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.


### 2.0 Recommendations

Provided the petitioner submits revised Sections B and F, HED concludes that the toxicological, residue chemistry , and ORE database s support the establishment of the proposed Section 3 Registrations and the permanent tolerances listed in Section 2.2.2.

2.1 Data Deficiencies/Data Needs

Residue Chemistry: The following field rotational crop residue data conducted as specified in OPP TS 860.1900 are requested (trials should employ a seasonal rate of 0.228 lb ai/acre): sweet corn

- NAFTA Growing Zones 1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1); cotton

- Nort American Free Trade Agreement ( NAFTA ) Growing Zones 6 (n=1), 8 (n=4), and 10 (n=3). These data were previously requested and remain outstanding (D397075, T. Bloem, 20

- Dec

- 2011). If the petitioner would like to permit rotation to sweet corn and cotton following application at a higher rate and/or different interval, then a full set of field rotational crop data conducted at the desired rate and interval should be submitted. The additional data are requested so as to ensure that the resulting rotational crop tolerances are reflective of conditions for growers in all relevant regions. Based on the existing sweet corn and cotton field rotational crop residue data (residues ≤0.035 ppm) and the unrefined nature of the current dietary exposure analyses ( ≤31 % aPAD; ≤51 % cPAD), HED concludes that the requested data will not have a significant effect on the human

- health risk assessment.

In addition, the ruminant feeding study monitored for residues of only flutriafol with the residues of concern ( ROC ) for risk assessment estimated using factors derived from the ruminant metabolism study. The factors range from 2

- 77x and reflect the fact that parent was not the major residue in some of the matrices. In order to facilitate refinements in the dietary exposure analysis which may be necessary as part of future registrations, HED advis es the petitioner to analyze the ruminant feeding study samples for some or all of the ROC for risk assessment (storage stability data will also be required). HED notes that the rum inant residue estimates employed in the dietary analyses are conservative as they are comparable to, or significantly higher than, the TRRs from the metabolism study (30 ppm dietary burden) and due to the conservative nature of the dietary burden calculations.

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 7 of 38 

### ORE: In accordance with the updated Part 158 data requirements (2007), one or more Dislodgeable Foliar Residue (DFR) studies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 S tandard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR 

### ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational post

- application assessments. Of the analyzed DFR studies, the maximum F A R 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislod ged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 12

- Dec

- 2 012, Exposure Science Advisory Council). A DFR study is not required for flutriafol at this time since the dermal MOEs are greater than 4 times the LOC (i.e., 400) based on default values for the fraction of application rate available for transfer after a foliar application.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Tolerance Enforcement Method

- Plants: Adequate methods are available to enforce the currently established plant tolerances (D362421, T. Bloem, 11

- Mar

- 2009; D340513, T. Bloem, 11

- Mar

- 2009; D388603, T. Bloem, 16

- Jun

- 2011). The flutriafol method employed in the magnitude of the residues studie s is based on the current tolerance enforcement method. Based on this and since adequate method validation data were provided as part of the magnitude of the residue studies, HED concludes that the current tolerance enforcement method is adequate to enfor ce the tolerances associated with this petition. In addition, the QuEChERS method has been shown to adequately quantify residues of flutriafol ( http://www.crl

p esticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf ).

Tolerance Enforcement Method

- Livestock: Method ICIA AM00306 (revisions of 13

- Aug

2007 and 8

- Oct

- 2007) has been determined to be sufficient for enforcement of the currently established rumi nant and hog meat byproduct tolerances (D362421, T. Bloem, 11

- Mar

- 2009). The flutriafol method employed in the ruminant magnitude of the residue studies is based on this method. Based on this and since adequate method validation data were provided as par t of the magnitude of the residue study, HED concludes that the current tolerance

- enforcement method is adequate to enforce the tolerances associated with this petition.

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 8 of 38 

### 2.2.2 Recommended Tolerances

Table 2.2.2.1 is a summary of the proposed and HED

- recommended tolerances for residues of flutriafol per se . A revised Section F is requested.

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

Strawberry 1.5 1.5 Based on the available field trial data and the Organization of Economic Cooperation and Development ( OECD ) tolerance

calculation procedure

, the indicated tolerances are recommended (excluding wheat grain). For wheat grain, the OECD tolerance

- calculation procedure recommended a 0.10

- ppm tolerance but this value was increased to 0.15 ppm to harmonize with Codex. In addition, based on the available data a wheat bran tolerance of 0.20 ppm would have been recommended but this va lue was increased to 0.30 ppm to harmonize with Codex.

HED notes that the currently established field corn grain and popcorn RAC and processed commodity tolerances are appropriate to cover the proposed label amendments. Based on 40 CFR 180.1(g), a tolera nce on wheat covers triticale. Wheat, forage 30 30 Wheat, hay 15 15 Wheat, straw 9 9.0 Wheat, grain 0.10 0.1 5

W heat, bran

-- 0. 3 0

W heat, germ

-- 0.25 Triticale, grain 0.10

-- Corn, field, forage 1 5.0 5.0 Corn, field, stover 1 15 15 Corn, pop, stover 1 15 15 Peanut, hay 15 15

Almond hull 15 15 Based on the field tri a l data and the OECD tolerance calculation procedure, a 15

- ppm tolerance is recommended.
Almond 0.6 0.60

Based on the field trial data and the OECD tolerance

calculation procedure, pecan and almond tolerance s of 0.02

ppm and 0.60 ppm were recommended. Since the recommended tolerances are not within 5x, HED concludes that a crop group tolerance is inappropriate.

The ChemSAC was consulted to determine if the almond and pecan tolerances may be translated to the remaining crops within the tree nut crop group 12

- 14 (almond and pecan are the representative crops) . The ChemSAC determined that the

pecan tolerances may be translated to the tree nut crops it

represen ts but requested th e submission of pistachio residue data to determine if translation of the almond data is appropriate (ChemSAC minutes 22

- Jun

- 2011). Since the pistachio data has not been submitted, HED is recommending for tolerances in/on almond, pecan, and those tree nuts which are represented by pecan. Pecan 0.015

0.02 African tree nut 0.015
Brazil nut 0.015
Bur oak 0.015
Butternut 0.015 Cajou 0.015
Cashew 0.015
Castanha

- do

- maranhao 0.015
Coconut 0.015 Coquito nut 0.015
Dika nut 0.015
Guiana chestnut 0.015
Hazelnut 0.015
Heartnut 0.015 Hickory nut 0.015 Japanese horse

- chestnut 0.015
Macadamia nut 0.015 Mongongo nut 0.015 Monkey

- pot 0.015
Pachira nut 0.015 Sapucaia nut 0.015 Walnut, black 0.015 Walnut, English 0.015

Vegetable, cucurbit, group 9 0.20 0.30 Based on the available field trial data and the OECD tolerance

- calculation procedure, tolerances in/on cucumber, muskmelon, and summer squash of 0.15 ppm, 0.3 ppm, and 0.15 ppm, respectively, were determined to be appropriate. Since the tolerances are wit hin 5x, HED recommends that a crop group tolerance at 0.30 ppm be established.

### Flutriafol Human

- Health Risk Assessment D4 11360

Page 9 of 38 

### Table 2.2.2.1: Tolerance Summary.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

Vegetable, fruiting, group 8

- 10 0.60 1. 0 Based on the available field trial data and the OECD tolerance

- calculation pro cedure , tolerances in/on tomato, bell pepper, and nonbell pepper of 0.6 ppm, 0.3 ppm, and 0.6 ppm, respectively, were determined to be appropriate. Since the tolerances are within 5x, a crop group tolerance at 0.60 ppm would be appropriate. However, a toleranc e of 1.0 ppm is recommended in order to harmonize with a Codex MRL in/on sweet pepper.

Tomato, paste 1.5 1.5 Based on the field trial and processing data, a tolerance in/on tomato paste is required. Hog, fat

-- 0.01

Based on the livestock maximum reasonable dietary burden ( MRDB ) and the feeding studies, HED concludes that the recommended tolerances are appropriate.

The currently established meat byproduct (cattle, goat, horse, sheep) tolerances should be deleted. Hog, muscle

-- 0.01 Cattle, liver 1.0 0.80 Cattle, meat byproducts, except liver 0.10 0.05 Cattle, muscle 0.03 0.05 Cattle, fat

-- 0.05 Goat, liver 1.0 0.80 Goat, meat byproducts, except liver 0.10 0.05 Goat, muscle 0.03 0.05 Goat, fat

-- 0.05 Horse, liver 1.0 0.80 Horse, meat byproducts, except liver 0.10 0.05 Horse, muscle 0.03 0.05 Horse, fat

-- 0.05 Sheep, liver 1.0 0.80 Sheep, meat byproducts, except liver 0.10 0.05 Sheep, muscle 0.03 0.05 Sheep, fat

-- 0.05 Milk 0.01 0.01

1 The currently established field corn forage / stover tolerances and popcorn stover tolerances should be increased to the indicated levels.



### 2.2.3 Revisions to Petitioned

- For Tolerances

See the comments column of Table 2.2.2.1.

2.2.4 International Harmonization

There are no C anadian or Mexican maximum residue limits (MRLs) in/on the proposed commodities (see A ttachment 1). T he re are Codex MRLs for residues of flutriafol in/on peanut hay (20 ppm), dried chili peppers (10 ppm), sweet peppers (1 ppm), wheat straw (8 ppm), wheat grain (0.15 ppm), and wheat bran (0.3 ppm). The wheat grain and wheat bran tolerances are harmonized an d HED determined that harmonization of the US fruiting vegetable with the Codex sweet pepper MRL was appropriate (HED does not set tolerances in/on dried pepper). Harmonization of the peanut hay and wheat straw tolerances were determined to be unnecessary as these commodities do not normally enter international commerce.

2.3 Label Recommendations

Provided a revised Section B is submitted which specifies the following rotational crop restrictions, HED concludes that the proposed application scenarios ar e supported by the available data: (1)

a pplication r ates ≤0.225 lbs ai/acre /season

- labeled crops may be planted immediately and cotton and sweet corn may be planted 18 0 days after application ; rotation to any other crop is prohibited and (2) application r ates >0.225 lbs ai/acre /season

- treated field may only be rotated to a labeled crop.

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### 3.0 Ingredient Profile

3.1 Chemical Identity

The chemical structure and nomenclature of flutriafol and the triazole metabolites are presented in Tables 3.1.1

.

T able 3.1.1: Flutriafol Nomenclature

.

Chemical structure

Common name Flutriafol Company experimental name PP450 (ICI/Syngenta until 2001) ; CHA 1310

- 05 (Cheminova code)
IUPAC name ( RS )

- 2,4’

- difluoro

- α

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)benzhydryl alcohol
CAS name (±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol CAS registry number 76674

- 21

- 0

1,2,4

- triazole (T) triazolylalanine (TA) triazolylacetic Acid (TAA)



### 3.2 Physical/Chemical Properties

Table 3.2.1 is a summary of the physical/chemical properties for flutriafol.

T able 3.2.1: Physicochemical Properties of Flutriafol. Melting point/range

-- Not available pH 6.1 in a 1% aqueous dilution CSF for Flutriafol Technical dated 3/23/07 Density 0.99 g/cm 3 Water solubility 95 mg/L at 20 oC

PP#7F7197 administrative materials Solvent solubility At 21 oC g/L 1,2

- Dichloroethane 19

- 20 Acetone 116

- 135 Ethyl acetate 29

- 34 Methanol 115

- 134

n

- Heptane <10 Xylene <10 Vapor pressure 4 x 10

- 7 Pa at 20 oC Dissociation constant, pK a 2.3 at 25 oC Log(K OW ) log P OW = 2.3 at 20 oC UV/visible absorption spectrum

-- Not available

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### 3.3 Proposed Use Pattern

Cheminova requested Section 3 Registrations for application of fl utriafol to strawberries, cucurbit vegetables, fruiting vegetables, tree nuts, wheat, and triticale. In addition

, the petitioner is requesting the following amendments to the peanut, field corn, and popcorn registrations: (1) removal of the peanut hay feeding restriction and (2) reduction in the current 80

- da y PHI for field corn and popcorn forage, stover, and grain to 0 days for forage and 7 days for stover and grain.

Table 3.3.1 is a summary of the end

- use products and target pests and Table 3.3.2 is a summary of the proposed application scenarios. The p roposed labels also specify the following: (1) 12

- hour REI except for d etasseling field corn where a 5

- day REI is proposed ; (2) applicators and other handlers must wear long

- sleeved shirt and long pants, chemical

- resistant gloves, and shoes plus socks; ( 3 ) application through irrigation is prohibited; ( 4 ) treated fields may be rotated to a labeled crop immediately after application and to cotton or sweet corn 180 days after application; rotation to any other crop is not allowed ; ( 5 ) adjuvants may be added to the spray solution ; and ( 6 ) for ground application, the minimum spray volume is 10 gallons per acre (GPA) ; for aerial application, the minimum spray volume is 10 GPA for tree nuts, 2 GPA for corn and wheat, and 5 GPA for all other crops.

Provided a revised Section B is submitted which specifies the following rotational crop restrictions, HED concludes that the proposed application scenarios are supported by the available residue chemistry data: (1) a pplication r ates ≤0.225 lbs ai/acre /season

- label ed crops may be planted immediately and cotton and sweet corn may be planted 18 0 days after application ; rotation to any other crop is prohibited and (2) application r ates >0.225 lbs ai/acre /season

- treated field may only be rotated to a labeled crop.

Table 3 .3.1: Summary of End

- Use Products.
Trade Name Conc. Formulation Label Date Target Crops Target Pests

Topguard® Fungicide (EPA Reg. No. 67760

- 75) 1 1.04 lb

ai/gal suspension

concentrate (SC) not

indicated field corn popcorn gray leaf spot, southern corn blight, northern leaf blight, common rust, southern rust, eyespot, anthracnose leaf blight

wheat Rust, powdery mildew, leaf and glume botch, fusarium head

blight (suppression)

peanut early/late leaf spot, peanut rust, leaf scorch, pepper spot, web

blotch, and suppression of white mold/southern stem rot cucurbits (excluding muskmelon) powdery mildew, gummy stem blight, and target spot

fruiting vegetables powdery mildew, anthracnose, cercospora leaf spot

tree nuts scab, shot hole, powdery mildew, alternaria leaf and fruit

spot, anthracnose, shothole, eastern filbert blight, brown rot blossom blight, leaf rust, downy spot, zonate leaf spot Flutriafol® 250 g/L Fungicide (EPA Reg. No. 67760

- 120) 1 2.08 lb

ai/gal suspension

concentrate (SC) not

indicated muskmelon powdery mildew

strawberry powdery mildew

1 Full and supplemental labels for each were submitted.

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### Table 3.3.2: Summary of Proposed Application Scenarios

. App. Timing ; Type ; and Equip. Formulation Single App. Rate ( lb ai/acre ) Max. # . App.

per Season Max. Seasonal

App. Rate ( lb ai/acre ) PHI

(days) Use Directions and Limitations

corn (field corn, field corn grown for seed, and popcorn)

postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.057

- 0.114 2 0.228 0

- forage 7

- stover/grain - An adjuvant may be used prior to the V8

growth stage and after the VT growth stage.

- 7

- day retreatment interval (RTI).

- Apply no later than the R4 stage (early dough stage) wheat (spring and winter) and triticale
postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.081

- 0.114 2 0.228 0

- forage 15

- hay 30

- grain - 7

- day RTI

peanuts
postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.057

- 0.114 4 0.455 7

- 14

- day RTI

strawberry
postemergence foliar broadcast

spray SC

(2.08 lb ai/gal) 0.081

- 0.114 4 0.455 0

- 7

- day RTI

muskmelons (true cantaloupe, cantaloupe, casaba, Crenshaw melon, golden pershaw melon, honeydew melon, honey balls, mango mel on, Persian melon, pineapple melon, Santa Claus melon, and snake melon
postemergence foliar broadcast

spray SC

(2.08 lb ai/gal) 0.081

- 0.114 4 0.455 0

- 7

- day RTI

cucurbit vegetables (excluding muskmelons): chayote (fruit), Chinese waxgourd, citron melon, cucumber, gherkin, edible gourd (includes hyotan, cucuzza, hechima, Chinese okra), Momordica spp. (includes balsam apple, balsam pear, bittermelon, Chinese cucumber), pumpkin, summer squash, winter squash ( includes butternut squash, calabaza, hubbard squash, acorn squash, spaghetti squash), and wate rmelo n postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.081

- 0.114 4 0.455 0

- 7

- day RTI

fruiting vegetables (excluding tomatoes): African eggplant, bell pepper, eggplant, martynia, non

- bell pepper, okra, pea eggplant, pepino, roselle, scarlet eggplant; cultivars and/or hybrids of these)
postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.114 4 0.455 0

- 7

- day RTI

bush tomato, cocona, currant tomato, garden huckleberry, goji berry, groundcherry, narnajilla, sunberry, tomatillo, tomato, tree tomato; cultivars and/or hybrids of these
postemergence foliar broadcast

spray SC

(2.08 lb ai/gal) 0.114 4 0.455 0

- 7

- day RTI

African tree nut, Brazil nut, bur oak, butternut, cajou, cashew, castanha

- do

- maranhoa, coconut, coquito, dika, Guiana chestnut, hazelnut, heartnut, hickory nut, Japanese horse

- chestnut, macadamia nut, monogongo nut, monkey

- pot, pachira nut, pecan, and sapu caia nut
postemergence foliar broadcast

spray SC

(1.04 lb ai/gal) 0.057

- 0.114 4 0.455 14

- 7

- day RTI

almonds and walnuts
postemergence foliar broadcast

spray SC

(2.08 lb ai/gal) 0.057

- 0.114 4 0.455 14

- 7

- day RTI

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### 3.4 Anticipated Exposure Pathways

Based on the proposed/registered flutriafol application scenarios

, dietary exposure is an anticipated exposure pathway as residues of flutriafol may be found in/on crops, livestock commodities, and drinking water . E xposure in the residential ( non

- occupati onal ) setting is not anticipated

. B ased on the registered/proposed application scenarios and the results of a fish bioaccumulation study, residues in fish/shellfish are expected to be insig nificant ( D407105, T. Bloem, 27

- Mar

- 2013 ; this includes consumptio n at the subsistence level ). The current action is expected to result in short

- and intermediate

- term occupational exposures (handler and post

applica tion)

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established pr ocedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residen tial setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are an alyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patt erns among specific subgroups.

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### 4.0 Hazard Characterization and Dose

- Response Assessment

No new toxicity and/or metabolism data have been received since the last flutriafol risk assessment (D405792, T. Bloem et al. , 27

- March

- 2013). The following flutri afol toxicological information is a summary of the information presented in D382902 (K. Lowe et al. , 19

- Oct

2011).

Since the last risk assessment, HED’s Hazard and Science Policy Committee (HASPOC) evaluated all existing hazard and exposure data, as wel l as current use patterns for flutriafol, and concluded using a weight

- of

- evidence approach that a subchronic inhalation toxicity study is not required at this time (TXR# 0056856).

4.1 Absorption, Distribution, Metabolism, & Elimination (ADME)

Flutriaf ol is quickly absorbed, extensively metabolized, and quickly eliminated (within 48 hours) regardless of sex, dose, or whether exposure was to single or multiple dosing regimens. More than 78% of the dose was recovered in the bile and urine. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal glands, spleen, and pituitary. The total amount of radioactivity isolated in the tissues and carcass was <1

- 3%. Bioaccumulation was considered unlikely. The parent was isolated in only trace amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism. The primary site for metabolism was the 2

- fluorophenyl ring. The initial metabolic step was epoxidation followed by rearrangement to form either the dihyd rodiol isomers or the hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated. A second, minor route for metabolism of flutriafol was via the removal of the triaz ole ring to form 1

- (2 fluorophenyl)

- 1

- (4

- fluorophenyl)

- ethandiol, which is then conjugated with glucuronic acid.

An in vivo rat dermal

- absorption study (MRID # 47090415) is available for flutriafol that is acceptable and indicates that the absorption is 1 7%, 21%, and 11%, respectively, at 2, 20, and 200 μg/cm 2 

### , following a 10

- hour exposure. A value of 21% is appropriate (most protective) for dermal risk assessments.

4. 2 Toxicological Effects

Flutriafol is a member of the conazole triazole class of pesti cides. The triazole fungicides inhibit C14

- demethylase, a fungal cytochrome P450, which plays a role in sterol production. Sterols, such as ergosterol, are needed for fungal membrane structure and function, and are essential for the development of functi onal cell walls. Mammals, particularly humans, also express cytochrome P450 enzymes (hepatic and extra

- hepatic). Thus, exposure to chemicals such as flutriafol in sufficient quantities may lead to toxicity.

Flutriafol is categorized as having high ora l acute toxicity in the mouse (Category II). It is categorized as having low acute toxicity via the oral, dermal and inhalation routes (Categories III, III and IV, respectively) in rats. Flutriafol is minimally irritating to the eyes (Category III) and i s not a dermal irritant (Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method).

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### Short

- term, subchronic, and chronic toxicity studies in rats, mice, and dogs identified the liver as the primary target organ of flutriafol. Hepatotoxicity was first evident in the subchronic studies (rats and dogs) in the form of increases in liver enzyme release (alkaline phosphatase), liver weights, and histopathology findings ranging from hepatocyte vacuolization to c entrilobular hypertrophy and slight increases in hemosiderin

- laden Kupffer cells. It is noteworthy that with chronic exposures, there are no indications of progression of liver toxicity in all species. After over one year of exposure, hepatotoxicity in r ats, dogs, and mice took the form of (1) minimal to severe fatty changes; (2) bile duct proliferation/cholangiolar fibrosis; (3) hemosiderin accumulation in Kupffer cells; (4) centrilobular hypertrophy, and (5) increases in alkaline phosphatase release. Slight indications of effects in the hematopoietic system are sporadically seen in the database. These effects are manifested in the form of slight anemia (rats and dogs) and increased platelet, white blood cell, neutrophil, and lymphocyte counts (mice). These effects, however, were minimal in severity.

In a 28

- day dermal toxicity study, there were no signs of toxicity for flutriafol up to the limit dose (1000 mg/kg/day).

The potential impact of in utero and perinatal flutriafol exposure was investigated in three developmental toxicity studies (two in rats, one in rabbits) and two multi

- generation reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, a quantitativ e susceptibility was observed ( delayed ossification or non

- ossification of the skeleton in the fetuses) at a lower dose than maternal effects. In the second rat developmental study, a qualitative susceptibility was noted. Although developmental toxicity occurred at the same dose level that elicited maternal toxicity, the developmental effects (external, visceral, and skeletal malformations; embryo lethality; skeletal variations; a generalized delay in fetal development; and fewer live fetuses) were more s evere than the decreased food consumption and body

- weight gains observed in the dams. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. In the two

- generation reproduction studies, a qualitativ e susceptibility was also seen. Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the systemic toxicity of the parental animals (decreased body weight and food consumption and liver toxicity).

Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and subchronic neurotoxicity studies at the highest dose only. These effects, however, were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity. This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity in any additional short

- term studies in rats, mice, and dogs, or in the long

- term toxicity studies in rats, mice, and dogs. It is also important to note that in the acute neurotoxicity study, for animals that did not die in the s tudy or were sacrificed in extremis, all effects resolved by Day 8.

In the guideline immunotoxicity study for flutriafol, there was no evidence of immunotoxicity up to the highest dose tested.

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### All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Several triazoles are carcinogenic. Even though SAR analysis indicates that flutriafol has the potential to produce thyroid and/or liver tumors in rodents, neither the chronic/carcinogenicity study in rats or the carcinoge nicity study in mice revealed treatment

- related increases in tumor incidences.

4. 3 S afety F actor for Infants and Children (FQPA SF)

The RAB1 risk assessment team concluded that the FQPA SF could be reduced to 1x based on the following considerations outlined in more detail in the sections below: 1) the toxicology database for flutriafol is adequate for risk assessment; 2) f lutriafol is not considered neurotoxic; 3) clear NOAELs are established to protect for the fetal/offspring effects observed; and 4) the exposure databases are sufficient and are unlikely to underestimate exposure.

4.3 .1 Completeness of the Toxicology Database

The toxicology database for flutriafol is adequate for quantification of risk for di etary, residential, and occupational uses and FQPA SF evaluation. The following acceptable studies are available for evaluation: developmental toxicity studies in rats (2) and rabbits (1), two

generation reproduction studies in rats (2), and acute and su bchronic neurotoxicity studies in rats.

4.3 .2 Evidence of Neurotoxicity

There is no concern for neurotoxicity with flutriafol. Signs of neurotoxicity were reported in the acute and subchronic neurotoxicity studies at the highest dose only; however, t hese effects were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity. In addition, there was no evidence of neurotoxicity in any additional short

- term studies in rats, mice, and dogs, or in th e long

- term toxicity studies in rats, mice, and dogs. A developmental

- neurotoxicity study ( DNT ) study is not required.

4.3 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no concerns or residual uncertainties for pre

- and/or post

- natal toxicity. There is evidence for increased qualitative susceptibility in a prenatal study in rats and rabbits and the two generation reproduction study in rats; however, there is no concern for these observations since: 1) clear NOAELs and LOAELs were established in the fetuses/offspring; 2) the dose

- response for these effects are well defined and characterized; 3) developmental endpoints are used for assessing acute dietary risks t o the most sensitive population (females 13

- 49) as well as all other short

- and intermediate

- term exposure scenarios; 4) the acute reference dose for females 13

- 49 is 1000

- fold lower than the dose at which quantitative susceptibility in the first developme ntal rat study was observed; and 5 ) the chronic reference dose is greater than 300

- fold lower than the doses at which the offspring effects were observed in the two

- generation reproduction studies

.

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### 4.3 .4 Residual Uncertainty in the Exposure Database

The re are no residual uncertainties in the exposure database. The dietary exposure assessment is conservativ e in nature (utilizes tolerance

- level residues and 100% crop treated ). In addition, there are no proposed or registered residential uses.

4.4 Toxici ty Endpoint and POD Selections

The points of departure, uncertainty factors, and toxicity endpoints for dietary exposure assessment and occupational exposure assessment are presented in Table s 4.4 .1 and 4.4 .2, respectively.

Acute Dietary Endpoint (General Population): The acute neurotoxicity screening battery in the rat was selected for the acute dietary endpoint for the general population. An uncertainty factor ( UF ) of 100 x ( 10x for interspecies extrapolation

, 10x for intraspecies variability , an d 1x for FQPA SF ) was applied to the NOAEL of 250 mg/kg to generate the aRfD of 2.5 mg/kg for the general population. The LOAEL is 750 mg/kg based on decreased body weight, body

- weight gain, absolute and relative food consumption, agonal effects in both s exes (dehydration, urine

- stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, and scant feces), in males (red or tan perio ral substance, chromodacryorrhea, chromorhinorrhea, labored breathing, and slight ataxia), and in females (piloerection and bradypnea). This study is appropriate for the expected duration of exposure, and is protective for potential neurotoxic effects due to acute exposure to flutriafol.

Acute Reference Dietary Endpoint (Females 13

- 49 years old): The prenatal developmental toxicity study in rabbits was selected for the acute dietary endpoint for females 13

- 49 years of age. An UF of 100 x ( 10x for intersp ecies extrapolation

, 10x for intraspecies variability , and 1x for FQPA SF ) was applied to the developmental NOAEL of 7.5 mg/kg to generate the aRfD of 0.075 mg/kg for females 13

- 49 years of age. The developmental LOAEL of 15 mg/kg is based on decreased nu mber of live fetuses, complete litter resorptions and increased post

- implantation loss. The NOAEL selected provides the lowest NOAEL from any toxicity study in the flutriafol database in which a toxic response could be the outcome of 1

- 2 days of single do sing. The only other studies considered for this endpoint were the prenatal developmental studies in rats, where the developmental NOAELs was 10 mg/kg in both studies with developmental LOAELs of 50 mg/kg/day (1982) and 75 mg/kg/day (2008) . The rabbit st udy is therefore protective of the effects seen in these rat studies and provides the most protective endpoint for the population of concern (pregnant females and fetuses).

Chronic Dietary Endpoint (RfD): The chronic dog toxicity study was selected for the chronic dietary endpoint for the general population. An UF of 100 x ( 10x for interspecies extrapolation

, 10 x for intraspecies variability , and 1x for FQPA SF ) was applied to the NOAEL of 5 mg/kg/day to generate the cRfD of 0.05 mg/kg/day for the genera l population. The LOAEL is 20 mg/kg/day based upon adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, and triglycerides), increased adrenal cortical vacuo lization of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes, mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males, and initial body

- weight losses, decreased c umulative body

weight gains, and increased adrenal weights in the females. This NOAEL is lower than any

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### NOAEL in the database for chronic effects. In addition, the study duration is appropriate for the duration of exposure. Both the 28

- rat and 90

- day d og oral toxicity studies provide similar NOAEL/LOAEL value s and toxic effects (adverse liver effects) as the chronic dog study. Other studies considered for this endpoint were the chronic/carcinogenicity studies (mouse and rat), as well as the 2

- generatio n reproduction studies where similar effects were seen at slightly higher doses.

Short

- and Intermediate

- Term Dermal and Inhalation Endpoint: The prenatal developmental toxicity study in rabbits was selected for the short

- and intermediate

- term dermal an d inhalation endpoints. The developmental NOAEL is 7.5 mg/kg/day and the LOAEL is 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post

implantation loss. Although maternal and developmental toxicity were observed at the same dose, the maternal effects were restricted to moderate decreases in bodyweight and food consumption, and were less severe than the effects observed in the offspring. In addition, although decreased body weight was an adverse effect o bserved in non

- pregnant animals with flutriafol, results of this study indicate that pregnant animals were more sensitive to this effect. The route

- specific 28

- day dermal toxicity study was also considered for dermal exposures , but there was no toxicity o bserved up to the limit dose (1000 mg/kg/day) and developmental effects were not evaluated

. T his study provides the most protective endpoint for the populations of concern (pregnant females and fetuses). The only other studies considered for this endpoin t were the 90

- day dog and the 2

- generation reproduction studies (parental effects) where liver toxicity (the target organ) was observed at similar doses. However, the severity of these liver effects does not increase with duration, and, thus, the fetal mo rtalities in the rabbit study are considered

more severe. The level of concern for the dermal and inhalation endpoints is 100 based upon a 10x for interspecies extrapolation

, and a 10x for intraspecies variability

. Using a dermal

absorption factor of 21%, the dermal

- equivalent NOAEL is ~35.7 mg/kg/day (NOAEL of 7.5 mg/kg/day / 21% dermal absorption = 35.7 mg/kg/day).

Cancer Classification and Risk Assessment Recommendation : F lutriafol is classified as “Not likely to be Carcinogenic to Humans” based on the results of the carcinogenicity studies in rats and mice.

4. 5 Recommendation for Combining Routes of Exposure for Risk Assessment

Since the POD/endpoint for short

- and intermediate

- term dermal and inhalation endpoints are identical, exposure via these routes may be aggregated.

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### Table 4.4 .1: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and Non

Occupational Human Health Risk Assessments. Exposure/ Scenario POD Uncertainty/FQPA SFs RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) NOAEL =

250 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 2.5

mg/kg/day

aPAD = 2.5 mg/kg/day Neurotoxicity screening battery

– rat; LOAEL = 750

mg/kg, based on decreased body weight, body

- weight gain, absolute and relative food consumption, and clinical signs of toxicity in both sexes: dehydration, urine

- stai ned abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea.
Acute Dietary (Females 13

- 49 years of age) NOAEL = 7.5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0.075

mg/kg/day

aPAD = 0.075 mg/kg/day Developmental study

– rabbit; Developmental LOAEL =

15 mg/kg, based on decreased number of live fetuses, complete litter resorptions and increased post

- implantation loss.

Chronic Dietary (All Populations) NOAEL = 5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.05

mg/kg/day cPAD = 0.05 mg/kg/day Chronic toxicity

– dog; LOAEL = 20 mg/kg/day, based on

adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, al bumin, and triglycerides), increased adrenal cortical vacuolation of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males; and initial body weight losses, decreased cumulative body

- weight gains, and increased adrenal weights in the females. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and mice.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginni ng of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to hu man (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.



### Table 4. 4. 2: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Occupational Human Health Risk Assessments. Exposure/ Scenario POD UFs LOC Risk Assessment Study and Toxicological Effects

Dermal Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term NOAEL= 7.5 mg/kg/day

1 Dermal

- absorption factor = 21% UF A = 10x UF H = 10x Occupational

LOC for MOE = 100 Developmental toxicity

– rabbit; Developmental

LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post

- implantation loss.

Inhalation Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term NOAEL = 7.5 mg/kg/day

Inhalation toxicity assumed to be equivalent to oral toxicity

2 I nhalation

- absorption factor = 100% UF A = 10x UF H = 10x Occupational

LOC for MOE = 100 Developmental toxicity

– rabbit; Developmental

LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post

- implantatio n loss.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and

mice.

1 Dermal absorption factor was derived from the dermal penetration study (MRID 47090415).

2 Inhalation absorption factor is considered the worst

- case scenario for inhalation exposure using an oral NOAEL ( D372347, K. Lowe et al. , 16

- Dec

- 2009 ). Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = le vel of concern.

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### 5.0 Dietary Exposure and Risk Assessm ent D4 15068 , T. Bloem, 2 3

- Apr

- 201 4 ( residue chemistry summary for the current action) D4 17188 , T. Bloem, 2 3

- Apr

- 201 4 ( dietary exposure analysis for the current action )



### 5.1 Metabolite/Degradate Residue Profile

Based on the available apple sugar beet, rapeseed, poultry, and ruminant metabolism studies and the confined rotational crop studies, HED concludes that the residue of concern for tolerance enforcement, in the proposed/registered primary crops, rotational crops, and livestock, is flutriafol. The residues of concern for risk assessment are defined in Table 5.1.1

. HED note s that if the poultry and/or ruminant die tary burden exceeds the level employed in the metabolism studies,

m etabolism studies conducted a t this higher dietary burden with [carbinol

14 

### C]flutriafol and [triazole

- 3,5

- 14 

### C]flutriafol may be required.

Table 5 .1

. 1: Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.

Matrix R OC 1
Risk Assessment Tolerance Enforcement coffee, soybean seed, fruit, sugar beet

, cucurbit vegetables, fruiting vegetables, and tree nuts flutriafol, T, TA, and TAA

flutriafol (free) cotton (Section 18 use) 2 , peanut, and cereal grains flutriafol (free and conjugated), defluorinated flutriafol, T, TA, and TAA ;

c ombined flutriafol (free and conjugated) and defluorinated flutriafol residues may be estimate by multiplying the free flutriafol residues by 2.2 x 5

rotational crops (excluding dried roughage feed commodities) flutriafol (free and conjugated), M28, T, TA (free and conjugated), TAA, and TLA ; combined flutriafol (free and conjugated) and M28 residue may be estimated by multiplying the free flutriafol residue by 1.3x 5

rotational crops (dried roughage feed commodities) same as that mentioned above but with multiplication of the free flutriafol residues by 2. 0 x to account for the combined residues of flutriafol (free and conjugated) and M28 poultry 3 flutriafol

, T, TA

, and TAA

ruminan t 4 flutriafol , M3, M3e, M4, M7, M10, T, TA

, and TAA ; combined flutriafol, M3, M3e, M4, M7, and M10 residues may be estimated by multiplying the free flutriafol residue by the following 5 : skim milk

- 58x, cream

- 15x,

liver, 5.3x, kidney 77x, muscle

- 6x, and fat

- 2x

wat er flutriafol and T

-- 1 See A ppendix B for names and structures of the metabolites. Separate risk assessments are required for T and TA/TAA/TLA; these compounds have been determined to be toxicologically different from flutriafol.

2 Decision will be reevaluated if a Section 3 use is requested (additional data may be required).

3 HED notes that if the poultry dietary burdens increase, then these conclusions will be revisited and poultry metabolism studi es conducted as specified in OPPTS 860. 1300 with [carbinol

14 C]flutriafol and [triazole

- 3,5

- 14 C]flutriafol may be required.

4 HED notes that if the ruminant dietary burden increases, then these conclusions will be revisited and ruminant metabolism studies conducted as specified in OPPTS 860. 1300 with [carbinol

14 C]flutriafol and [triazole

- 3,5

- 14 C]flutriafol may be required.

5 The indicated factors are based on results from the metabolism stud ies or confined rotational crop study.

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### 5.2 Food Residue Profile

The following paragraphs are summaries of the available magnitude of the residue data for the registered crops, proposed crops, rotational crops, and livestock.

Registered Primary Crops: Adequate magnitude of the residue data have been submitted to

sup port the current ly

- estab lished tolerances.

Magnitude of the Residue

- Proposed Crops : The petitioner submitted adequate strawberry, cucurbit vegetable, fruiting vegetable, and tree nut field trial data which employed the proposed application scenario (adequate tomato processing data were also submitted). The geographical representation of the data satisfy the requirements specified in OPPTS 860.1500 and the analytical methods and storage intervals have also been validated. Based on these data

, the OE CD tolerance

- calculation procedure, and taking into consideration the international residue limits, HED concludes that the plant tolerances listed in Table 2.2.2.1 for residues of flutriafol

per se are appropriate.

The petitioner previously submitted and HED reviewed adequate field corn (translated to popcorn), wheat (translated to triticale), and peanut field trial data which employed the proposed application scenario (adequate field corn, wheat, and peanut processing data were also submitted; D388603, T . Bloem, 16

- Jun

- 2011). These data satisfied the geographical data requirements specified in OPPTS 860.1500 and the analytical methods and storage intervals were also validated. Due to uncertainties concerning the nature of the residue in ruminants at the dietary burden associated with these uses, HED concluded that the feeding of peanut hay should be prohibited and recommended for the field corn and popcorn uses provided the PHI was increased to 80 days (petitioner withdrew the wheat use). HED notes that the currently

- established field corn grain, popcorn grain, and peanut nutmeat raw agricultural commodity (RAC) and processed commodity tolerances reflect the proposed application scenario.

As part of the current petition, adequate ruminant metabolism/f eeding studies were submitted which employed dietary burdens that encompass the maximum reasonably balanced diets (MRBDs) associated with the proposed field corn, popcorn, wheat, and peanut application scenarios. Based on these data, HED concludes that th e livestock tolerances listed in Table 2.2.2.1 for residues of flutriafol per se are appropriate.

Magnitude of the Residue

- Rotational Crops : The proposed label indicate s that treated fields may be rotated to a labeled crop at anytime and to cotton and sweet corn 180 days after application; rotation to any other crop is not permitted. In support of the 180

- day plant

- back interval (PBI), the petitioner cited previously submitted and reviewed sweet corn and cotton field rotational crop data which emp loyed an application rate of 0.228 lb ai/acre and resulted in the establishment of tolerances for residues in/on these crops at 0.01

- 0.09 ppm. Adequate field rotational crop data conducted at seasonal rates >0.228 lb ai/acre are not available. Based on t he available data, HED concludes that the following rotational crops restrictions are appropriate (revised Section B is requested): (1) a pplication r ates ≤0.225 lbs ai/acre /season

- labeled crops may be planted immediately and cotton and sweet corn may be planted 18 0 days after application ; rotation to any other crop is prohibited and (2) application r ates >0.225 lbs ai/acre /season

- treated field may only be rotated to a labeled crop.

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### In order to fulfill the geographical data requirements specified in OPPTS 860.1500 for sweet corn and cotton, HED requests that the petitioner submit the following additional field rotational crop data (trials should employ a seasonal rate of 0.228 lb ai/acre): sweet corn

- NAFTA Growing Zones 1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1); cotton

- NAFTA Growing Zones 6 (n=1), 8 (n=4), and 10 (n=3). These data were previously requested and remain outstanding (D388603, T. Bloem, 16

- Jun

- 2011). If the petitioner would like to permit rotation to sweet corn and cotton fo llowing application at a higher r ate and/or a different interval, then a full set of field rotational crop data conducted at the desired rate and interval should be submitted.

Magnitude of the Residue

- Livestock : The petitioner previously submitted an adequate poultry feeding study and, as part of the current request, the petitioner submitted an adequate dairy cattle feeding study (D340513, T. Bloem, 11

- Mar

- 2009). Based on these data and the current MRBDs, HED concludes that the ruminant tolerances li sted in Table 2.2.2.1 are appropriate. Based on the hog MRBD and the dairy cattle feeding study submitted as part of the current request, the established hog meat byproduct tolerance remains appropriate. Based on the available data, residues poultry comm odities are anticipated to be insignificant (180.6(a)(3)).

5.3 Drinking Water Residue Profile

Table 5 .3.1 is a summary of worst case flutriafol per se surface

- /ground

- water estimated drinking water concentrations (EDWCs) when considering all pr o posed/registered uses ( EFED; D 412882

, J. Wolf, 29

- Oct

- 201 3 ). The water estimates were incorporated directly into the dietary exposure analysis via the water sources direct (all sources) and indirect (all sources) commodities. The water models and their d escription are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5 .3.1 : Maximum Flutriafol EDWCs.

Model Application Rate Concentration (ppb)

Groundwater ( PRZM

- GW 1 ) stone fruit ( 4 x 0.114 lbs ai/acre at 7 day intervals) acute 310 grape (6 x 0.081 lbs ai/acre at 14 day intervals) chronic 202

Surface water (FIRST 2 ) Apples (6 x 0.114 lbs ai/acre at 7 day intervals) 3 acute 4 0.55 chronic 4.03

1 Pesticide Root Zone Model

- Groundwater (PRZM

- GW)

. 2 FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1)

. 3 The initially proposed application rate for apple.

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### 5.4 Dietary (Food + Drinking Water) Risk Assessment

The following text concerns exposure and risk to flutriafol and those metabolites identified as being toxicologically the same as flutriafol. For information concerning exposure and risk to T and TA/TAA/TLA, which HED has determined to be toxicologically different from flutriafol, see the Aggregate Section (7.0).

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCID ( ver. 3.16) which incorporates the food consumption data from USDA NHA NES/WWEIA ( 2003

- 2008). The acute and chronic analyses assumed tolerance

- level residues or tolerance

- level residues adjusted to account for the residues of concern for risk assessment , 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted which indicate that tolerances for residues in/on apple juice, grape juice, dried prunes, and tomato puree are unnecessary and since tolerances for residues in/on raisin and tomato paste tolerances are established /recommended , the DEEM (ver

. 7.81) default processing factors for these commodities were reduced to 1. The DEEM (ver. 7.81) default processing factors were retained for the remaining relevant commodities. The resulting acute ( ≤31 % aPAD; female s 13

- 49 years o ccupied the highest % of the aPAD ) and chronic ( ≤51 % cPAD; children (1

- 2 years old) had the highest exposure ) dietary risk estimates are not of concern to HED. Table 5.4 .1 is a summary of the acute and chronic dietary risk estimates.

Tab le 5.4.1: Summary of the Acute and Chronic Dietary Exposure and Risk.

Population aPAD

(mg/kg/day) Exposure

(mg/kg/day) 1 %aPAD 1 cPAD (mg/kg/day) Exposure

(mg/kg/day) %cPAD

General U.S. Population

2.5 0.02 7487 1 .1

0.05 0.0 08896 18 All Infants (< 1 year old) 0.0 65963 2. 6 0.0 19913 40

Children 1

- 2 years old 0.0 60251 2. 4 0.0 25382 51
Children 3

- 5 years old 0.0 46566 1. 9 0.0 18434 37

Children 6

- 12 years old 0.0 29389 1 .2 0.0 10803 22

Youth 13

- 19 years old 0.0 20440 <1 0.0 06565 13

Adults 20

- 49 years old 0.0 22428 <1 0.00 7519 1 5

Adults 50

- 99 years old 0.0 20955 <1 0.00 7621 1 5

Females 13

- 49 years old 0.075 0.0 23031 31 0.0 07469 1 5

1 95 th percentile (tier 1 analysis)

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### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential uses proposed or currently registered for flutriafol. Therefore, residential handler and post

- application exposure/risk were not assessed.

6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for flutriafol. The Agency h as been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to devel op the best spray drift management practices (see the Agency’s Spray Drift website for more information; http://www.epa.gov/opp00001/factsheets/spraydrift.htm ) The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift ® and chemical specific properties of pesticides. The p otential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

6

. 2 Residential Bystander Post

- Application Inhalation Exp osure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for flutriafol at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low vapor pre ssure (3.0 x 10

- 9 

### mmHg, 20°C). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pe sticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate p ost

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for flutriafol.

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### 7.0 Aggregate Exposur e/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Because there are no uses for flutriafol which result in residential (non

- occupational) exposures, the aggregate assessment need only consider food and water. Since the dietary exposure analysis included both food and water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acut e and chronic exposure to flutriafol and those metabolites identified as being toxicologically identical to flutriafol. All aggregate flutriafol risk estimates are not of concern to HED.

Application of flutriafol also results in exposure to T and TA / TA A / TLA . These compounds are considered to be toxicologically different from flutriafol. HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than HED’s level of concern (D 414952 , T. Morton

, 24

- Oct

- 201 3 ). The proposed new uses and label amendments do not require a revision to this m ost recent aggregate assessment.

8.0 Cumulative Exposure/Risk Characterization

Flutriafol is a member of the triazole

- containing class of pesticides. Althoug h conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common mec hanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological responses is found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altere d DNA methylation. It is not clearly understood whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not fo llowing a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.e pa.gov/pesticides/cumulative

.

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### 9.0 Occupational Exposure/Risk Characterization D416213, K. Lowe, 24

- Jan

- 2014



### Based on the proposed new uses , it has been determined that the potential exposure scenarios that will need to be assessed include short

- and in termediate

- term occupational exposures (handler and post

- applica tion)

. The proposed changes to the field corn, field corn grown for seed, and popcorn application scenarios do not impact the use pattern or application rate, and, therefore, a revised occupa tional exposure assessment is not required. The previous corn assessment determined that

, provided applicators were gloves and a 5

- day REI is established for detasseling corn, the resulting MOEs were not of concern to HED ( D383037, K. Lowe, 20

- Sep

2011); these restrictions are on the proposed label.

It is HED policy to use the best available data to assess exposure. Several sources of generic data were used in this assessment as surrogate data in the absence of ch emical

- specific data, including the Pes ticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and the Agricultural Reentry Task Force (ARTF) database . Some of these data are proprietary, and subject to the data protection provisions of FIFRA. A dditional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website ( http://www.epa.gov/pesticides/science/handler

exposure

- data.html )

.

9.1 Handler Risk Assessment

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. Based on the anticipated use patterns, and the current labeling regarding types of equipment and techniques that can be used, occupation al hand ler exposure is expected

. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: (1) mixing/loading liquids for aerial, groundboom, and airblast applications; (2) applying sprays via aerial, air blast and groundboom equipment; and (3) flagging for aerial applications. Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar.

The occupational handler exposure a nd risk estimates indicate that the short

- and intermediate

term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE > 100) with the use of chemical

- resistant gloves as personal protective equipment as directed by the label

. At the ba seline level of personal protection (i.e., no gloves and no respirator), only one scenario results in a risk estimate below the LOC with a combined (dermal + inhalation) MOE of 82; this scenario is mixing/loading a liquid formulation for aerial application to high acreage crops. With the addition of gloves, the combined dermal + inhalation MOE is 470, which is not of concern. All other scenarios result in risk estimates greater than 220 with baseline attire. Table 9.1.1 is a summary of the handler e xposu re and risk estimates.Page 27 of 38



### Table 9 .1.1 : Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flutriafol

.

Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/ acre) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Total

(LOC = 100)

Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Aerial app

. of liquid formulation Cucurbits, Pecans (and other tree

nuts), Almonds and Walnuts, Peppers (and Other Fruiting Vegetables), Tomatoes, Strawberry 220 (baseline)

0.219

(baseline) 0.114 350 0.0267 280 0.000127 59,000 280

Cotton, Wheat (spring and winter) and Triticale, Sorghum 1200 0.0916 82

0.000435 17,000 82

37.6 (single layer w/gloves) 0.0156 480 470

Groundboom

app

. of liquid formulation Cucurbits, Pecans (and other tree

nuts), Almonds and Walnuts, Peppers (and Other Fruiting Vegetables), Tomatoes, Strawberry

220 (baseline) 0.114 80 0.00612 1,200 0.000029 260,000 1,200

Wheat (spring and winter) and Triticale, Sorghum 200 0.0153 490 0.0000723 100,000 490

Cotton 0.26 200 0.0347 220 0.000165 45,000 220 Airblast app

. of liquid formulation Pecans (and other tree nuts), Almonds and Walnuts 0.114 40 0.00304 2,500 0.0000145 520,000 2,500

Applicator

Aerial spray

app

. Brassica (cole) leafy vegetables, Celery, Leafy Vegetables, Cucurbits, Pecans (and other tree nuts), Almonds and Walnuts, Peppers (and Other Fruiting Vegetables), Tomatoes,

Strawberry 2.08 (engineering control) 0.0049

(engineering control) 0.114 350 0.000253 30,000 0.00000284 2,600,000 30,000

Cotton, Wheat (spring and winter) and Triticale, Sorghum 1200 0.000867 8,700 0.00000971 770,000 8,600

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Page 28 of 38 Table 9 .1.1 : Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flutriafol

.

Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/ acre) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Total

(LOC = 100)

Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Groundboom

spray app

. Cucurbits, Pecans (and other tree

nuts), Almonds and Walnuts, Peppers (and Other Fruiting Vegetables), Tomatoes, Strawberry 78.6 (baseline) 0.34

(baseline) 0.114 80 0.00218 3,400 0.0000449 170,000 3,300

Wheat (spring and winter) and Triticale, Sorghum 0.114 200 0.00545 1,400 0.000112 67,000 1,400

Cotton 0.26 200 0.0124 600 0.000257 29,000 590

Airblast

spray app

. Pecans (and other tree nuts), Almonds and Walnuts 1770 (baseline) 4.71

(baseline) 0.114 40 0.0246 300 0.000312 24,000 300

Flagger

Flagger for aerial spray

app

. Cucurbits, Pecans (and other tree nuts), Almonds and Walnuts, Peppers (and Other Fruiting Vegetables), Tomatoes, Strawberry

, Cotton, Wheat (spring and winter) and Triticale,

Sorghum 11 (baseline) 0.35

(baseline) 0.114 350 0.00134 5,600 0.000203 37,000 4,900

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: Baseline, PPE (gloves) , Eng. Controls.

2 Based on proposed label s (Reg. No. 67760

- REN

, 67760

- 75

, 67760

- REA ).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A/day) × DAF ( 21 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal NOAEL ( 7.5 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A / day) ÷ BW ( 69 kg).

7 Inhalation MOE = Inhalation NOAEL ( 7.5 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL ( 7.5 mg/kg/day) ÷ ( Dermal Dose + Inhalation Dose )

.

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### 9.2 Post

- Application Risk Assessment

HED uses the term post

- application to describe exposures (inhalation and dermal) that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

- entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activ ity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for p ost

application exposure.

9.2.1 Inhalation Post

- Application Risk Assessment

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for flutriafol at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( 3.0 x 10

- 9 

### mmHg, 20°C ). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing pos t

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to vola tilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for flutriafol

.
Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed fo r occ upational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application inhalation exposure. Therefore, it is expected that these handler inhalation exposure esti mates would be protective of most occupational post

- application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting of tree nuts is another potential source of post

- application inhalation

exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechanical harvesting activities. The non

- cancer inh alation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100).

### Flutriafol Human

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Page 30 of 38 

### 9.2.2 Dermal Post

- Application Risk Assessment

Short

- and intermediate post

- application dermal exposure is anticipated for the proposed crops with expected scenarios and resulting exposures and MOEs summarized in Table 9 .2.2. 1

. All scenarios resulted in MOEs greater than the LOC of 1 00 (ranging from 2 30 to 4 ,600 ) on day 0 (12 hours after application ; proposed REI ) and, therefore, are not of concern to HED.

Table 9.2.2.1: Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Flutriafol

.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) Proposed

Application Rate (lb ai/A) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(LOC = 100)

Short

- and Intermediate

- term

Cucurbits Hand

- set Irrigation 1,900

0.114 0.32 0.015 510
Pecans (and other tree nuts), Almonds and Walnuts Hand harvesting 1,400 0.011 690

Peppers (and Other Fruiting Vegetables), Tomatoes Hand

- set Irrigation 1,900 0.015 510

Wheat (spring and winter) and Triticale Scouting 1,100 0.009 880

Strawberry Hand harvesting 1,100 0.009 880

Sorghum Scouting 210 0.002 4,600

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day.

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (21%)]  BW (69 kg).

3 MOE = POD (7.5 mg/kg/day) / Daily Dermal Dose.



### 9.2.2 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of flutriafol

. Flutriafol has low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III and IV). Flutriafol is minimally irritating to the eyes (Toxicity Category III) and is not a dermal irritant (Toxicity Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CFR 156.208(c)(2)(iii), ai’s classified as Acute III or IV for acute dermal, eye irrita tion and primary skin irrigation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to flutriafol

.

RDI: RAB1 ( 22

- Feb

- 201 4 ) T. Bloem:S10945:Potomac Yard 1:703

- 605

- 0217:7509P:RAB1

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Chemical Names and Structures

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### Appendix A. Toxicology Profile and Executive Summaries

The requirements (40 CFR 158.340) for food uses for flutriafol are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Study Requirements for Food Uses for Flutriafol
Study Technical Required Satisfied
870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes

no yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21

- Day Dermal 870.3250 90

- Day Dermal 870.3465 90

- Day Inhalation yes yes yes

no

no yes

yes yes

-

- 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

— Oth er Genotoxic Effects yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no

no yes yes

no -

- yes yes

- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes yes yes yes

yes yes Special Studies for Ocular Effects

Acute Oral (rat) Subchronic Oral (rat) Six

- month Oral (dog) no

no

no -

-

-

Table A.2: Acute Toxicity Profile

– Flutriafol. Guideline No. Study Type MRID(s) Results Toxicity Category
870.1100 Acute oral (rat) 47090336 LD 50 = 1140 mg/kg (M); 1480 mg/kg (F) III 870.1100 Acute oral (mouse) 47090335 LD 50 = 365 mg/kg bw (M); 179 mg/kg bw (F) II 870.1200 Acute dermal (rat) 4786101 LD 50 >2000 mg/kg bw III 870.1300 Acute inhalation (rat) 47090338 LC 50 >5.20 mg/L IV 870.2400 Primary eye irritation (rabbit) 47090339 Minimally irritating III 870.2500 Primary dermal irritation (rabbit) 47090341 Not a dermal irritant IV 870.2600 Dermal sensitization (mouse) 47090343 Not a sensitizer

-

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Page 32 of 38 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3050 28

- Day oral toxicity

(rat) 47090344 (1982)

Acceptable/non

- guideline 0, 100, 300, 800, 2000, or 5000 ppm (0, 10, 30, 80, 200, and 500 mg/kg/day) NOAEL = 800 ppm (80 mg/kg/day). LOAEL = 2000 ppm (200 mg/kg/day), based on liver toxicity (increased weight, centrilobular hepatocellular hypertrophy, fatty change, hydropic degeneration, smooth endoplasmic reticulum proliferation, and increased aminopyrine

- N

- demethylase activity) in both sexes and decreased body

- weight gain and food consumption in males. 870.3100 90

- Day oral toxicity

(rat) 47090345 (1982)

Acceptable/guideline 0, 20, 200, or 2000 ppm M: 0, 1.5, 14, and 158 mg/kg/day) F: 0, 1.6, 22, and 145 mg/kg/day NOAEL = 200 ppm (14/22 mg/kg/day in M/F) LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on decreased body

- weight gain, decreased food consumption and liver toxicity (increased absolute and adjusted liver weights, increased endoplasmic reticulum proliferation in the males, and increased APDM activity).

870.3150 90

- Day oral toxicity

(dog) 47090346 (1982)

Acceptable/guideline 0, 1, 5, or 15 mg/kg bw/day NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day, base d on adverse liver findings (increases in organ weight, alkaline phosphatase, aminopyrine N

- demethylase activity, and incidence of hemosiderin

- laden Kupffer cells) in both sexes, spleens with hemosiderin content slightly higher than controls in the males, and decreased cumulative body

- weight gains and increased triglycerides in the females. 870.3200 28

- Day dermal toxicity

(rat) 47090347 (2007)

Acceptable/guideline 0, 250, 500, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day. LOAEL was not established.

870.3700a Prenatal developmental

(rat) 47090349 (1982)

A cceptable/guideline 0, 10, 50, or 125 mg/kg/day Maternal NOAEL = 50 mg/kg/day. LOAEL = 125 mg/kg/day, based on increased incidence of ventral/genital staining of the fur and decreased maternal body

- weight gains and food consumption. Developmental NOAEL = 10 mg/kg/day. LOAEL = 50 mg/kg/day, based on delayed ossification or

non

- ossification of the skeleton in the fetuses. 870.3700a Prenatal developmental

(rat) 47521303 (2008)

Acceptable/guideline 0, 2, 5, 10, or 755 mg/kg/day Maternal NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on decreased body

- weight gains and food consumption. Developmental NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on increased late resorptions; malformations (cleft p alate and multiple hyoid malformations) and variations in the hyoid; variations in the maxilla/mandible, rudimentary and long cervical ribs, pelvic girdle, and radius/ulna; numerous skeletal retardations detailed above and corresponding decrease in fetal w eights. 870.3700b Prenatal developmental

(rabbit) 47090350 (1982)

Acceptable/guideline 0, 2.5, 7.5, or 15 mg/kg/day Maternal NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased corrected and uncorrected body

- weight gains and food consumption. Developmental NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post

implantation loss.

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Page 33 of 38 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3800 2

- gen. reproduction and

fertility effects (rat) 47090351 (1986)

Acceptable/guideline 0, 60, 240, or 1,000 ppm M: 0, 4.8, 20.6, and 88.7 mg/kg/day) F: 0, 5.5, 21.9, and 103 mg/kg/day Parental/Systemic NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreas ed body

- weight gains and food consumption and on effects on the liver (increased liver weights, centrilobular hypertrophy, and fatty change). Reproductive NOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]). LOAEL was not determined. Offspring NOAEL = 240 ppm (20. 6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased live birth index and litter size and on effects on the liver (fatty change/vacuolization). 870.3800 2

- gen. reproduction and

fertility effects (rat) 48196921, 48196922 (2009)

Acceptable/guideline 0, 30, 80, 150, 300, 1000 ppm 0, 1.8/2.2, 4.8/5.85, 9/10.8, 18.5/22.6, and 62.8/ 77.1 mg/kg bw/day [M/F] Parental/Systemic NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Parental/Systemic LOAEL = 300 ppm (18 .2/22.6 mg/kg bw/day [M/F]) based upon increased relative liver weights, fatty deposits in the liver in both sexes as well as hepatocellular hypertropy in males. Reproductive NOAEL = 300 ppm (18.2/22.6 mg/kg bw/day [M/F]. Reproductive LOAEL was not obser ved. Offspring NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Offspring LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day [M/F]) based upon increased pup mortality in the F1 pups at the first litter check and 0

- 4 postnatal days. 870.4100 Chronic toxicity (1

year; dog) 47090353 (1988) Acceptable/guideline 0, 1, 5, or 20 mg/kg/day NOAEL = 5 mg/kg/day. LOAEL = 20 mg/kg/day, based on: adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkal ine phosphatase, albumin and triglycerides), increased adrenal cortical vacuolization of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and re d blood cell count) in the males; and initial body weight losses, decreased cumulative body

- weight gains, and increased adrenal weights in the females. 870.4200 Carcinogenicity

(mouse) 47090354 (1988)

Acceptable/guideline 0 (two control groups), 10, 50, or 200 ppm M: 0, (0, 1.1, 5.9, and 24 mg/kg/day) F: 0, 1.4, 7.4, and 31 mg/kg/day NOAEL = 50 ppm (5.9/7.4 mg/kg/day in M/F). LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on hepatotoxicity (increased fatty change) in both sexes. No evidence of carcinogenicity

870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 47090352 (1986)

Acceptable/guideline 0, 20, 200, or 2000 ppm M: 0, 1.02, 10.0, and 102 mg/kg/day) F: 0, 1.27,12.2, and 122 mg/kg/day NOAEL = 200 ppm (10.0/12.2 mg/kg/day in males/females). LOAEL = 2000 ppm (102/122 mg/kg/day in males/females), based on adverse liver effects (increased liver weights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hypertro phy), and clinical chemistry findings. No evidence of carcinogenicity

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Page 34 of 38 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5100 In vitro Bacterial Gene

Mutation (Salmonella typhimurium)/ mammalian activation gene mutation assay 47090401 (1988)

Acceptable/guideline 0, 1.6, 8, 40, 200, 1000, or 5000 μg/plate ( Trial 1) or 0, 8, 40, 200, 1000, 2500, or 5000 μg/plate (Trial 2); Both trials were performed w/wo S9

- activation There were no marked increases in the mean number of revertants/plate in any strain. There was no evidence of induced mutant coloni es over background.

870.5300 In Vitro Gene Mutation

assay in mouse lymphoma cells 47090402 (1986)

Acceptable/guideline 0, 10, 33, 100, 333, or 1000 μg/mL (+S9, Trial 1); 0, 150, 300, 450, 600, or 750 μg/mL (

- S9, Trial 1); 0, 150, 300, 450, 600, 750, 900, 1050, or 1200 μg/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700, or 800 μg/mL (

- S9, Trial 2) There was a dose

- related increase in mutant frequency (7.0

- 9.0x10

- 5 treated vs. 3.0x10

- 5 controls) and absolute mutant numbers (70

- 148 colonies/p late vs. 63 controls) at 100 μg/mL and above in Trial 1 and a marked increase in mutant frequency at 750 μg/mL (6.5x10

- 5 treated vs. 1.2x10

- 5 controls) in Trial 2 attributable to severe cytotoxicity (2% relative survival). However, the increases in mutant frequency did not achieve the threshold value for a positive response (>10x10

- 5 ) in either trial and there was no marked increase in absolute mutant numbers at 750 μg/mL in Trial 2. In the absence of S9, there were no marked increases in mutant frequency or absolute mutant numbers compared to controls in either trial. There was no convincing evidence of induced mutant colonies over background in the presence or absence of S9

- activation. 870.5300 In Vitro Gene Mutation

assay in mouse lymphoma cells 48196918 (2006)

Acceptable/guideline 0, 25, 50, 100, 200, 400 and 600 μg/mL (±S9, Trial 1); 0, 12.5, 25, 50, 100, 200, 300 or 400 μg/mL (

- S9, Trial 1); 0, 200, 300, 325, 350, 375, or 400 μg/mL (+S9, Trial 2) (

- S9, Trial 2) The mutagenicity criterion (thres hold) of 126 colonies per 106 cells above the solvent control was not reached for any valid data at any test concentration, with or without metabolic activation. Although linear regression analysis found a significant (p<0.05) dose dependent trend of the mutation frequency in Experiment 1 (culture 1, with metabolic activation), Experiment 2 (culture 1), and Experiment 3 (cultures 1 and 2), these statistical results were considered biologically irrelevant because the threshold for mutagenicity was not excee ded and all absolute values were within the range of historical negative and solvent controls. 870.5375 In vitro Mammalian

Cytogenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocytes) 47090403 (1989) Acceptable/guideline 0, 25, 125, or 250 μg/mL (+/

- S9) No significant increases in the numbers of cells with aberrations (excluding gaps) were observed in either donor in the presence or absence of S9. There was no evidence of chromosome aberrations induced over background in the

pre sence or absence of S9

- activation.

870.5385 In vivo Mammalian

Cytogenetics

– [Bone Marrow Chromosomal Aberration Test 47090404 (1982) Acceptable/guideline 0, 15, 70, or 150 mg/kg There was no evidence of chromosome aberration induced over background.

8 70.5395 In Vivo Mammalian

Cytogenetics

- Erythrocyte Micronucleus Assay in Mice 47090405 (1986) Acceptable/guideline 0, 93.8, or 150 mg/kg Decreased (p<0.01) polychromatic erythrocyte to normochromatic erythrocyte ratios (PCE:NCE) were observed in both doses at all time points, indicating that the test material was toxic to the bone marrow. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time. 870.5450 Dominant Lethal Assay

– Mice 47090406 (1982) Acceptable/guideline 0, 25, 50, or 100 mg/kg/day (total doses of 0, 125, 250, or 500 mg/kg) Mortality (3/15 males) was noted at 100 mg/kg/day during dosing. Slight decreases (p<0.05) in body weight were observed at 50 mg/kg/d ay and above during dosing. There

were no treatment

- related effects on fertility, mean number of implantations, or the number of early or late deaths. There was no time

- related positive response of increased

pre

- or post

- implantation loss compared to con trols.

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Page 35 of 38 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5550 Unscheduled DNA

Synthesis in Primary Rat Hepatocytes/Mammalia n Cell 47090407 (2003) Acceptable/guideline 0, 250, 500, or 1000 mg/kg The net nuclear grain (NNG) counts in the treated animals (

– 3.42 to

– 2.64) were well below the threshold of ≥5 NNG needed for a positive response, and no increase in the mean percent of cells in repair was observed. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. 870.6200a Acute neurotoxicity

screening battery 47090408 (2005)

Acceptable/guideline 0, 125, 250, or 750 mg/kg NOAEL = 250 mg/kg. LOAEL = 750 mg/kg, based on decreased body weight, body

- weight gain, absolute and relative food consumption, and clinical signs of toxicity, indicative of a moribund condition, in both sexes: dehydration, urine

- stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impai red or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea, and signs of neurotoxicity: hunched posture in females and ataxia in males. 870.6200b Subchronic

Neurotoxicity

– Feeding Study in Rats 47090410 (2007)

Acceptable/guideline 0, 500, 1500, or 3000 ppm (0/0, 28.9/32.6, 84.3/97.6, and 172.1/185.0 mg/kg/day [M/F]) NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]). LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based on decreased body

- weight gain, absolute and relative food consumption; and decreased hindlimb grip strength in males. 870.7485 Metabolism and

pharmacokinetics (rat) 47090414 (2004),

47090412 (2006) Acceptable/guideline 5 or 250 mg/kg More than 78% of the dose was recovered in the bile and urine. Absorption was similar between sexes and between single and multiple dose regimes. Absorption is extensive. The dose was mostly eliminated within 48 hours. Only 0.04

- 0.05% of the dose was found in the expired carbon dioxide. Most of the radioactivity was excreted in the bile (47

- 79% of the dose). The excretion profile was similar between sexes. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal glands, spleen, and pituitary. The distribution profiles were similar between species, dose level, and single vs. multiple dose regime. In the whole blood, the concentrations were proportional to the dose. The total amount of radioactivity isolated in the tissues and carcass was <1

- 3%. Bioaccumulation was conside red unlikely. The parent was isolated in only trace amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism. Metabolism profiles were similar between sexes. The metabolic profiles were similar regardles s of the matrix (feces, urine, or bile), the dose, and the sex. The primary site for metabolism was the 2

- fluorophenyl ring. The initial metabolic step was epoxidation followed by either rearrangement to form the dihydrodiol isomers or to form hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated. A second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form 1

- (2 fluorophen yl)

- 1

- (4

- fluorophenyl)

- ethandiol, which is then conjugated with glucuronic acid.

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– Flutriafol.

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7600 In vivo dermal

penetration (rat) 47090415 (2006)

Acceptable/guideline 0.002, 0.02, or 0.2 mg/cm 2 skin were tested (10 μl/cm 2 skin), and actual doses were 0.00208, 0.0201, and 0.2154 mg/cm 2 skin Dermal ranged up to 15.8% of the applied dose. Absorption was minimal with only 4 h of exposure. Absorbable radioactivity (radioactivity in the skin at the application site and the adj acent skin) was minimal in groups that were exposed for 10 h and evaluated for an additional 158 h post

- exposure. Thus, almost all of the dose isolated in the skin will be absorbed. Considering the sum of absorbable and absorbed doses, 4

- 37% of the appli ed dose was recovered in the treatment groups (11%). Absorption rate constants were calculated as 0.236, 0.190, and 0.072 h

- 1 for the 2, 20, and 200 μg/cm 2 dose groups. Absorption mechanisms were saturated at the high dose. The elimination half

- lives we re calculated to be 31, 30, and 37 h for the 2, 20, and 200 μg/cm 2 dose groups. A maximum of 36.56% of the applied dose was noted as absorbed/absorbable (observed after 24 h exposure to 2 μg/cm 2 ). The dose that is absorbed/absorbable following a 10 h exp osure is 16.54%, 21.31% and 11.39%, respectively, at 2, 20, and 200 μg/cm 2

. 870.7800 Immunotoxicity (mice) 48360301 (2011) Acceptable/guideline 0, 50, 250, 500, 1000 ppm [F] (0, 9 .8, 4 6

. 8

, and 208 mg/kg/day [F] Systemic NOEAL = 9.8 mg/kg/day Systemic LOAEL = 46.8 mg/kg/day) based on increased absolute and relative liver weights and hematological effects. Immunotoxicity NOAEL = 208 mg/kg/day Immunotoxicity LOAEL was not established.

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### Appendix B. Chemical Names and Structures

Common name Chemical name Chemical structure

Flutriafol (±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol

M1B 1

- (2

- fluoro

- 4

- hydroxyphenyl)

- 1

- (4

- fluorophenyl)

- 2

- (1 H

- 1,2,4

- triazol

- 1

- yl)ethanol

M28 glucoside of a flutriafol metabolite, possible a derivative hydroxylated on one phenyl ring 

### --

1,2,4

- Triazole (T) 1 H

- 1,2,4

- triazole

Triazolylalanine (TA) 2

- amino

- 3

- (1 H

- 1,2,4

- triazol

- 1

- yl)propanoic acid

Triazolylacetic acid (TAA) 1 H

- 1,2,4

- triazol

- 1

- ylacetic acid

Triazole lactic acid (TLA) 1,2,4

- triaole

- 1

- lactic acid

Hydroxy flutriafol glucuronide (HFG; M3) --

### Flutriafol Human

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Page 38 of 38 Common name Chemical name Chemical structure

Dihydroxy flutriafol (DHF; M3e) --

Flutriafol glucuronide (FG; M4)

--

Methoxy flutriafol glucuronide (MFG; M7) --

Flutriafol sulfate (FS; M10)

--